4Definition of ovarian poor responder: The definition of poor responders has varied throughout the medical literature .Three or fewer oocytes or follicles .Estradiol (E2) level below 500 pg/ml.Fewer than five oocytes retrieved in high gonadotropin dose cycles (at least 450 inter national IU of FSH with a peak E2 below 1000 pg/ml .Most literature on poor responders has utilized at least 450 IU of FSH, yet several studies in the 1990s confirmed no added benefit to gonadotropin dosing above 450 IU of hMG or FSH.
5POR definition(ESHRE) At least two of the following three features must be present:Advanced maternal age (≥ 40 years) or any other risk factor for POR.A previous POR (≤3 oocytes with a conventional stimulation protocol)An abnormal ovarian reserve test (i.e. AFC = 5–7 follicles orAMH=0.5–1.1 ng/ml) )POR definition(ESHRE)
6Poor responders – how to diagnose D2 FSHAFCAMHFOLLICLESE2HMGOOCYTES
7Diagnosis: Basal (day 3) FSH level day 10 FSH level of the clomiphene citrate (CC) challenge test.Serum basal FSHEstradiol levelsanti-Müllerian hormoneSonographic assessment of ovarian reserve including (ovarian volume & antral follicle count)Color Doppler of ovarianHowever, the most accurate predictor of a poor response cycle is a history of poor response to gonadotropins.
8Poor responders – BOLOGNA criteria from ESHRE ADVANCED AGE>40/OTHER RISK FACTORS FOR PORABNORMALORTPREVIOUSPOR
9Poor responders – how to sight them? AMHCostly testNot widely availableCycle independentBetter predictive valueCurrent role - controversialAFCSimple testGood inter- & intra- observer reproducibilityBefore starting stimulationBetter correlation with retrieval numberCurrent role – widely practisedAMHCostly testNot widely availableCycle independentBetter predictive valueCurrent role - controversialFSHMost commonly usedEasily availableD2 or D3higher values –predictiveFalse positive rate 5%SCREENING TEST!hormonesDynamic testsultrasoundultrasound
10Poor responders – how to manage them? Mini doseprotocolConventional Agonists protocol- Dampening of ovarian response to gonadotropin stimulationModifyStimulationProtocolAdjuvanttherapy“Stop”protocolShort/Ultra-short/Flare protocolMicro dose flareprotocol
11Poor responders – how to manage them? Antagonist protocol-decreases stimulation duration-fewer cancellations-lesser GonadotropinsModifyStimulationProtocol
12Poor responders – how to manage them? Growth HormoneEstradiolAdjuvanttherapyAndrogensCOC pillSoft Protocolsr- LHL-arginine, steroids, aspirin
13Poor responders – how to manage them? Potentiates effect of FSHPrevious poor responders have proven benefitCostlyNot widely availableNo consensus on dose / routeGrowth HormoneCase – Control design128 – 812U s/c Growth HormoneMore M-II oocytes, higher E2 levels, pregnancy rates
14Poor responders – how to manage them? Essential prohormone in follicular steroidogenesisImproves the ovarian micromilieuMicronised DHES – 25mg TID X 4monthsImproves pregnancy rates and reduces miscarriage ratesAndrogensDHES
15Poor responders – how to manage them? LH plays a role in follicular developmentFrom D8, IUBeneficial in a subset ofa. age >35,b. previous PORc. Antagonist cyclesImproves pregnancy ratesr- LH
16Treatment (Is There an Ideal Protocol?) There is no really efficient treatment that could solve the problem of poor ovarian response and the current question is still which is the ideal protocol for patients defined as “poor responders”?
17Gonadotropins :It is confirmed that the increase of FSH starting dose , does not result in higher pregnancy rates .It is found no differences between the starting dose of 300UI, 450UI, and 600 UI of gonadotropins in terms of retrieved oocytes, number of embryos obtained and pregnancy rates.Maximal dosing, currently set at 450 IU of FSH, should be started as early in the cycle as possible. The dose may then be reduced once adequate response has been established.
18HMG versus recombinant FSH Recombinant FSH (rFSH) was introduced in the mid-1990s, and was initially touted to improve stimulation and pregnancy rates when compared with the already available equivalent dose of hMG.More recent trials have suggested that hMG may have advantages for poor responders undergoing IVF, although the data are limited .Mixed protocols of rFSH and hMG have become popular to provide both a high FSH dose as well as some LH activity.
19The role of LH in stimulation protocols for poor responders LH stimulation is available as both a recombinant LH (rLH) and in the standard urinary hMG, which contains a 1:1 ratio of FSH and LH activity.Additional LH activity during stimulation for IVF can be obtained with low doses of urinary or recombinant hCG.LH activity has been postulated to be beneficial during early follicular recruitment by increasing FSH receptors, as well as maintaining follicular development during later follicular maturation by maintaining steroid precursors.
20Articles have looked at the role of LH, both recombinant as well as mixed protocols with hMG . One reviewer has suggested that hMG, due to its LH activity, slightly increases the pregnancy rates in IVF when compared with rFSH alone.Most reviews and meta- analyses of the role of LH, however, have been unable to confirm any benefit or detriment of LH to IVF pregnancy or LBRs.
21The role of adding LH to rFSH stimulation in IVF is even less well studied in poor responders. With the introduction of GnRH antagonists for poor responders, it has become clear that antagonists blunt the rise in E2 during rFSH- stimulated cycles. This decreased rise in E2 can be overcome with either hMG or rLH.however, no advantage in IVF outcome has been established.some authors have found a benefit to LH addition in stimulation protocols in older patients.
22GnRH Analogues : in poor ovarian reserve the options could be : To decrease the length of suppression by decreasing the duration of GnRH agonist use (short and ultrashort, mini- and microdose flareup regimens) .
231.GnRH agonist microdose flare protocols : It has been shown that a single dose of 25–50 µg of GnRH agonist given on cycle day 2 can increase both FSH and LH levels.The protocols utilizing minimal doses of GnRH agonists such as 20–50 µg twice daily (b.i.d.) for 2 days at the beginning of the cycle (microdose flare protocols) are usually combined with OCP pretreatment in the cycle prior to COH to prevent corpus luteum rescue .
24In retrospective studies: the use of microdose protocols in poor responders has shown improved cycle outcome with regards to the number of retrieved oocytes, percentage of patients undergoing embryo transfer, cancellation rates and pregnancy rates, when compared with traditional long GnRH agonist protocols.
252.GNRH antagonist:Advantages of the use of GnRH antagonist + gonadotropins are :Improvement of patient’s compliance.Decreased number of days of stimulation and of the amount of gonadotropin administered.Reduction of ovarian hyperstimulation syndrome (OHSS).GnRH antagonists are not administered during the stage of follicular recruitment and thus suppression of endogenous gonadotropins secretion is not present at that time .Most protocols commence GnRH antagonists when the mean diameter of the lead follicle reaches 14 mm and continue daily until human chorionic gonadotropin (hCG) administration.
26suitable protocol for poor responders: GnRH antagonists + gonadotropinsReason :GNRH antagonists in the mid-late follicular phase during ovarianstimulation prevent the premature LH surge while not causingsuppression in the early follicular phase, obtaining morenatural follicular recruitment without any inhibitory effectpossibly induced by the GnRH agonist.
27As a general : Employ flare protocols when using OCPs and Antagonist protocols when not pretreating with OCPs.
29Clomiphene flare protocols A flare of endogenous gonadotropins can be also achieved with early CC administration. In these cycles, endogenous LH surge can be blocked with GnRH antagonists .CC flare was shown to:Reduce cancellation ratesIncrease the number of oocytes retrievedResult in a higher implantation rateHigher pregnancy rates in poor responders.
30Concerns about The use of a CC flare : Endometrial suppression CC is commonly and successfully used both in minimal stimulation protocols and for its flare effect in high-dose protocols in poor responders who are undergoing freeze-all cycles.Its potential for negative endometrial effects during a fresh transfer cycle necessitates further study.
31Letrozole flare protocols Letrozole is a highly selective aromatase inhibitor that has been used in assisted reproductive technology.Mechanism:Blocking estrogen synthesis and decreasing its circulating levels →effect on the pituitary →increasing release of endogenous gonadotropins.
32In COH protocols :letrozole doses of 2.5–5.0 mg daily on day 3–7 of stimulation cycle + menotropins + GnRH antagonist.Addition of letrozole in poor response cycles can decrease the total dose of FSH used when compared with a long GnRH agonist protocol+having an advantage in antagonist cycles in poor responders.
33Dosing intervals for poor responders It has become common to offer b.i.d. dosing of hMG or FSH in poor responders.When using mixed protocols of hMG from vials and rFSH from a pen, the authors often recommend twice-daily injections .Despite no documented benefit from b.i.d. dosing, it continues to be popular, especially for mixed protocols in poor responders.
34Minimal stimulationMany studies have suggested that for poor responders, natural cycle IVF or IVF with minimal stimulation produces similar pregnancy rates as with full-dose gonadotropins .A significant problem with natural cycle IVF is the high cancelation rate; however, use of GnRH antagonists in the late follicular phase has shown promising results .
35In two studies including poor responders, similar pregnancy rates were found following minimal stimulation IVF when compared with full-dose gonadotropins with IVF, despite a lower number of oocytes retrieved and embryos transferred.To decrease the rate of cycle cancelation and premature LH surge, one study included supplementation with :GnRH antagonists and hMGAdministered 0.25 mg of GnRH antagonists and 75 IU rFSH daily until ovulation induction.
36Natural, clomiphene or letrozole only IVF One randomized trial showed that poor responders treated with natural cycles + ICSI had higher implantation rates but similar clinical pregnancy rates per cycle and per transfer as patients treated with full-dose gonadotropins .CC stimulation alone was far more successful than natural-cycle IVF.Letrozole has also been looked at as an adjuvant in minimal stimulation cycles employing a low dose of gonadotropins.
37Laboratory options in poor response cycles ICSI for low oocyte yield Poor responders typically produce fewer than five oocytes per retrieval.In couples with poor ovarian response and fertilization failure, ICSI could have a potential advantage over IVF.( Higher fertilization rate ).If either the oocytes appear immature, or the mature-appearing oocyte is immature after stripping, employing standard IVF for the remaining oocytes.An oocyte is considered immature when it is surrounded by corona radiata with a less dense cumulus oophorus.
38Preimplantation genetic screening for poor responders ( PGD ) Couples are at an increased risk of developing chromosomally abnormal embryos after unexplained repeated IVF failures or advanced maternal age .Therefore, preimplantation genetic screening (PGS) utilizing FISH has been studied for patients with :advanced maternal agerepeated miscarriagerepeated implantation failuresevere male factor infertility
39Clinical trials utilizing FISH technology decreased the LBRs in women of advanced reproductive age and poor responders, either due to damage to the embryos or inaccuracy of the testing.Newer methods such as comparative genomic hybridization (CGH) have been introduced with the ability to analyze the entire genome.
40Ideal day of transferIn poor responders where fewer oocytes and embryos are available for transfers, transferring embryos at an earlier cleavage stage appears to be beneficial.As a general rule, once the number of viable embryos is equal to the number planned to be transferred, further delay of transfer is likely to be more harmful than beneficial.The clinical pregnancy rates per oocyte retrieval and per embryo transfer were significantly higher in the day 2 embryo transfer group compared with day 3.
41Number of embryos for transfer Indication for increasing the number of embryos to transfer:advanced reproductive agepoor ovarian reservepoor responseASRM guidline:in women aged less than 35 years→→→ up to two embryosin women aged less than 38 years→→→ up to three embryosin women aged less than 41 years→→→ up to four embryos Even in poor responders.
42Donor oocytes Recommend oocyte donation IVF only for: poor responders with multiple failed IVF cyclesthose with a very poor prognosis prior to IVF.Very poor prognosis group includes :all patients over 43 years of ageany patient with an FSH over 15 mIU/mlan undetectable AMH.
43Number of newer procedures in ART that have a role in the management of poor responders: In vitro maturation (IVM)Cryopreservation of oocytesEmbryos from multiple retrieval cyclesCryopreservation of donor oocytes (egg banking )
44IVM IVM of human oocytes is a new procedure. Oocytes are retrieved at 8–12-mm size after either priming with a few days of FSH injections followed by hCG, or during a natural cycle followed by a hCG injection.The immature retrieved oocytes are then matured in vitro in special media.
45While IVM has been proposed for patients with : Polycystic ovary syndrome at high risk of OHSSCancer patients who may not undergo standard stimulationA few case reports have described success using IVM in poor responders.There are limited data on the use of IVM for poor responders, it may aid in cases that otherwise would have been cancelled.The accumulation of oocytes from several ovarian stimulation cycles or freeze all cycles , creates a similar situation as in normal responders.
46Oocyte banking:The use of cryo-banked oocytes in an ovum donation program may be a realistic option in the future, significantly increasing the efficiency of the donor process.The process of synchronizing the recipient with the donor has some drawbacks, including waiting lists and coordinating recipient schedule to the timing of the donor.
481.DHEA TO IMPROVE OVARIAN FUNCTION Increase antral folliclesIncrease no of mieotically active oocytesDecrease follicular atresiaIncrease ovarian steroidogenesisDHEA
492.Pre conditions the ovary for ovulation induction DHEA supplementation for production of estrogen in the ovariesImproves follicular dynamics- enhances aromatase activity required for improved E2 levelsBetter ovarian function in women with increased resistance to OI – increase no of oocytes and embryos favoring clinical pregnancies
511)Dehydroepiandrosterone (DHEA) The mechanism by which DHEA supplementation may increase oocyte yield in poor responders is unknown.1- Animal models support the theory that androgens might facilitate the response of the growing follicles to FSH.2-In humans, this may result in higher AFC in patients with higher ovarian androgen levels such as in patients with polycystic ovary syndrome. It can also be responsible for the exaggerated ovarian response to exogenous gonadotropins in COH.
523-Other theories include an increase of IGF-1 during gonadotropin stimulation, and improved follicular steroidogenesis . 4- In some studies, higher baseline testosterone levels were found to be associated with a higher number of oocytes retrieved and improved IVF outcomes . Older patients have been shown to have diminished levels of DHEAs and may benefit from achieving normal serum levels . 5-It has also been postulated that DHEA supplementation reduces follicular apoptosis, thereby increasing the pool of primordial follicles.
532)Simple cyst drainage prior to stimulation protocols : One of the most significant side effects of pituitary down regulation with GnRH agonists in COH protocols is ovarian cyst formation.The incidence of these cysts ranges from 8 to 53% .Formation of follicular cysts may be related to the endogenous gonadotropin flare in response to mid-luteal GnRH agonists.The impact of these ovarian cysts on IVF outcomes remains controversial.
54There is evidence of poor IVF performance in patients who form ovarian cysts in response to GnRH agonists in both poor responders and normal responders.The worst outcomes were found with:Hormonally inactive cysts greater than 15 mm .While follicular cyst formation prior to IVF is probably a poor prognosticator, further studies are required to determine whether to proceed, wait or drain the cyst prior to the cycle.
553)Addition of Estradiol in the Luteal Phase Addition of estradiol in the luteal phase ± GnRH antagonist →→→Decreases the risk of cycle cancellation & Increases the chance of clinical pregnancy in poor responder REASON: luteal estradiol priming could improve synchronization of the pool of follicles available to controlled ovarian stimulation.
574)Addition of Growth Hormone: MECHANISM:modulating the action of FSH on granulosa cells by upregulating the localsynthesis of insulin-like growth factor-I (IGF-I).Addition of GH significantly increased the probability of live birth in poor responders.
585)Addition of Aspirin: MECHANISM: Increased intraovarian vascularity→→improving delivery of gonadotropic or other growth factors required for folliculogenesis.On the other hand, impaired ovarian blood flow could contribute to poor ovarian response.Although some papers have reported some beneficial effects of aspirin from the day of embryo transfer others have failed to confirm these findings.
59On the basis of updated evidence: A low dose of aspirin has no substantial positive effect on the likelihood of pregnancy and it should not be routinely recommended for women undergoing IVF.
60The benefits & risk of precycle oral contraceptive pill or antagonist suppression combined with estrogen primingBENEFITS:OCP pretreatment in IVF protocols establishes:an estrogenic environmentincreases sex hormone-binding globulin levelsdecreasing follicular androgen levels →→→ may delay apoptosis.
61The progestin component of the OCP : suppresses luteinizing hormone (LH) and may synchronize follicular developmentleading to a more evenly sized follicular response.OCP pretreatment in GnRH agonist flare cycles can prevent an early rise in progesterone by eliminating the corpus luteum.It is also believed that OCPs cause less pituitary downregulation when compared with GnRH agonists used in a long protocol.
62RISKS:OCPs significantly prolong stimulation and increase the dose of gonadotropins .Pituitary suppression with OCPs may blunt a GnRH agonist or letrozole flare response in follicular phase.
64Double stimulationCombination of two stimulations in one menstrual cycle.Targeted for antral follicles in the follicular phase and luteal phase.Two chances of OPU in a single menstrual cycleAchieve more oocytes and viable embryosFET as a primary strategy(from March my clinic only do FET)
65Antral follicles Many antral follicules in the periovulation time. Sometimes more antral follicles inthe luteal phase than the earlyfollicular phase.For poor responders, it is goodopportunity to retrieve oocytes.
66luteal-phase ovarian stimulation • Targeted for the antral follicles after ovulation or OPU. • Higher progesterone milieu during ovarian stimulation • Protocol: letrozole and HMG
68• Our data show that luteal-phase ovarian stimulation is feasible for producing potential oocytes/embryos, with potential pregnancy outcomes in subsequent FETs • Advantages: No spontaneous LH surge • lower OHSS incidence
69How to do double stimulation in poor responders? ProtocolNatural cycle -luteal-phase ovarian stimulationMild stimulation-luteal-phase ovarian stimulation
73Double stimulation in poor responders • Double stimulation is a promising approach both for patients with poor responders, especially for the cases that repeatedly did not have retrieved or viable embryos using conventional IVF regimens, and for cancer patients needing emergency fertility preservation. • Advantages – More oocytes retrieval – Reduced cancel rate – More flexible stimulation protocol
76Evidence-based management of poor ovarian response in IVF Stratis Kolibianakis MD MSc PhD
77Management of poor responders Treatment of poor responders has been attempted with various methods in retrospective, prospective, studiesusing comparative and non-comparative designsMost studies are underpowered and single and thus useful conclusions are difficult to be drawnThere is a need for an evidenced based approach in the problem of treatment of poor responders
78Search strategy:MEDLINE (1966 to November 2009)EMBASE (1988 to November 2009)Cochrane Central Register of Controlled Trials(Cochrane Library Issue 1, 2009)Keywords :(“poor” OR “low” OR “slow” OR “inadequate” OR “suboptimal”)AND (“response” OR “responder” OR “ovarian reserve”)No language limitationsHand-searching
79Data extractionDemographictype of studynumber of patients includeddefinition of poor ovarian responseMethodologicalrandomization methodallocation concealmentProceduraltype of intervention examinedtype and protocol of ovarian stimulationOutcome dataclinical or ongoing pregnancy ratelive birth
80Inclusion criteria: Prospective parallel two -arm Randomized controlled trialFull manuscriptExclusion criteria:Quasi-randomization methods(sequential numbers, date of birth, allocation by week day)Participation of patients more than once in studies
81Definition of poor ovarian response: VariableRetrospective vs. Prospective
82Addition of :Growth hormone (GH) or GH-releasing factor (GHRF)PyridostigmineTransdermal testosteroneAspirinL-arginineAromatase inhibitorsModifications of the long GnRH-a protocolShort versus long GnRH agonist protocol
84Background GH enhances GHRF enhances : gonadotrophin effects on granulosa cells (Lanzone et al., 1992)GHRF enhances :gonadotrophin-induced steroidogenesiscyclic adenosine monophosphate formation (cAMP) (Doldi et al., 1996)
85RD: 17 % Growth hormone for poor responders GH Addition and live birth (CI 95% to 0.30)Kolibianakis et al 2009 HRU
86Single study (Howles et al., 1999) Addition of GHRF vs. No addition GHRF Addition:Single study (Howles et al., 1999)Addition of GHRF vs. No additionLive birth rate: 5.2% vs. 4.0%Rate difference: 1.2% (95% CI: -5.3 to +8.1)
87ConclusionsGH Addition: Beneficial effect on the probability of live birthGHRF Addition: No beneficial effect
88Background Acetylcholinesterase inhibitor Increase GH secretion by enhancing the action of acetylcholine(Delitala et al., 1988)
89Relevant study: Kim et al ., 1999 N: 70 patientsProtocol: GnRH agonist protocol and gonadotrophinsDefinition of poor response : < 3 oocytes retrieved and/or a minimum requirement of 50 ampoules of gonadotrophins in a previous failed IVF attemptOutcome: ongoing pregnancy / delivery rate
90Addition of pyridostigmine vs. no addition: Ongoing pregnancy/delivery rate: 8.6% vs. 22.9%Rate difference : -14.3% (95% CI:-31.4 to +3.2)
91Addition of pyridostigmine Conclusion:Addition of pyridostigminedoes not appear to improve the ongoing pregnancy / delivery ratein poor responders undergoing IVF
92beneficial effect on the number of small antral follicles BackgroundIdentification of androgens receptors by immunochemistry in the human ovary (Suzuki et al., 1994)Androgens play a critical role on follicular growth (Ryan et al.,1968)Convertion of androgens into estrogens by the aromatase activity of the granulosa cells (Harlow et al., 1988; Shaw et al., 1989)Rationale:beneficial effect on the number of small antral folliclesimprove ovarian sensitivity to FSH
93Relevant study: Massin et al.,2006 N: 53 patientsProtocol: GnRH-a/recombinant FSH (rFSH)Definition of poor response :E2 <1200 pg/ml on the day of HCG administration, < 5 follicles retrieved, in a previous IVF cycleOutcome : Delivery rate
94Addition of transdermal testosterone vs. placebo Delivery rate: 8.3% vs. 4%Rate difference: 4.3% (95% CI:-12.3 to +22.2)Massin et al.,2006
95Testosterone addition in poor responders treated by IVF Conclusion:Testosterone additionin poor responders treated by IVFdoes not appear to resultin an increased probability of pregnancyMassin et al.,2006
96Background: Beneficial effect of the addition of low-dose aspirin in: - patients with low uterine blood flow undergoing thawed ET(Wada et al., 1994)-oocytes donation recipients with a thin endometrium(Weckstein et al.,1997)Rationale:impaired ovarian blood flow (Battaglia et al ., 2000)
97Relevant study: Lok et al., 2004 N: 60 patientsProtocol: GnRH-a/HMGDefinition of poor response : recruitment of fewer than 3 mature follicles (≥17mm) in previous IVF attempt or presence of repeated high basal levels of FSH (>10IU/L)Outcome : clinical pregnancy rate
98Addition of Aspirin vs. placebo Clinical pregnancy rate: 3.33% vs. 6.77%Rate difference: -3.33% (95% CI: to )
99A beneficial effect of low-dose aspirin ConclusionA beneficial effect of low-dose aspirinin poor responders undergoing IVFis not currently supported
100BackgroundIncreased vascularization appears to play a critical role in the selection, growth and maturation of follicles in both natural and IVF cycles (Weiner et al.,1993)Nitric oxide (NO), a product of L-arginine, is an intra and intercellular modulator in many biologic processes, including ovarian physiologyNO participates in periovulatory vasodilatatory modulation of the ovarian blood flow in the rat (Ben-Shlomo, 1994)
101BackgroundNO play a role in follicular maturation and ovulation. (Anteby et al., 1996)L-arginine is involved in the formation of NO either by a calcium dependent or a cytokine-inducible NO synthatase (Moncada et al., 1991)
102Relevant study: Battaglia et al.,1999 N: 34 patients Protocol: flare-up GnRH-a/pFSHDefinition of poor response : at least one previous cycle cancellation due to E2<1100 pmol/l and/or < 3 follicles recruited by day 8 in a previous IVF cycleOutcome : cumulus-oocyte complexes (COCs), pregnancy rate
103Addition of L-arginine vs. placebo COCs: 4.1 ± 1.9 vs. 1.6 ± 0.5 Battaglia et al.,1999Addition of L-arginine vs. placeboCOCs: 4.1 ± 1.9 vs. 1.6 ± 0.5WMD: 2.5 (95% CI: 1.53 to 3.47)Pregnancy rate : 17.6% vs. 0%Rate difference: 17.6% (95% CI: -4.1 to +41.0)
104Addition of L-arginine: no beneficial effect Battaglia et al.,1999ConclusionAddition of L-arginine: no beneficial effect
105Background:The selective inhibition of aromatase:- prevents the overall production of estrogens and their negative feedbackon the hypothalamus- hypophysis axis-results in an increased pituitary production of FSH (Simpson et al .,2000)-may increase the production of follicular androgens,which might improve follicular sensitivity or stimulate IGF- 1(Giudice et al., 1992; Palter et al., 2001
106renders AI an attractive option for poor responders -induces ovulation in anovulatory PCOS women(Mitwally and Casper, 2000)-increases ovarian sensitivity to gonadotrophinsrenders AI an attractive option for poor responders(Mitwally and Casper, 2002)
107Relevant study: Goswami et al .,2004 N:38 patientsProtocol: long GnRH-a/rFSH protocolDefinition of poor response : Poor ovarian response was defined as one to three failed IVF attempts, in which less than two dominant follicles developedOutcome : pregnancy rate
108Goswami et al .,2004 Addition of aromatase inhibitors vs.placebo Pregnancy rate/ cycle: 23.1% vs. 24.0%Rate difference: -0.9% ( 95% CI to +29.0)
109does not appear to improve clinical pregnancy rate Goswami et al .,2004ConclusionLetrozole additiondoes not appear to improve clinical pregnancy ratein poor responders undergoing IVF
110Background: Different dosages of GnRH agonist Different protocols for GnRH agonist administrationhave been used to enhance pregnancy rates in patients with poor ovarian response.
111Relevant study: N: 63 patients Dirnfeld et al.,1999N: 63 patientsProtocol: standard long luteal protocol versus a stop agonist long protocol.In the stop agonist protocol administration of GnRH-a was initiated in the midluteal phase and was stopped upon adequate down- regulation.Relevant study:Garcia-Velasco et al.,2000N: 70 patientsProtocol: “stop” versus “non-stop” protocoli) non-stop protocol: GnRH-a long protocol/high doses of FSH+HMG or (ii) stop protocol: GnRH-a initiated in midluteal phase of the previous cycle and was stopped with the onset of menses, FSH+HMG doses similar to the non stop protocol
112Dirnfeld et al.,1999 Definition of poor response : Garcia-Velasco et al.,2000Definition of poor response :≤ 4 mature oocytes retrieved in at least one previous IVF cycle and/or a previous low response to COH, as evidenced by a peak E2 level of<2.000 pmol/LOutcome : ongoing pregnancy rateDefinition of poor response :development of less than three follicles ≥18mm in diameter in a previous IVF attempt and presence of basal FSH concentration <12IU/mlOutcome : pregnancy rate
113Ongoing pregnancy rate : 5.0% vs. 2.6% -Dirnfeld et al.,1999Stop agonist protocol vs. standard long protocolOngoing pregnancy rate : 5.0% vs. 2.6%Rate difference: 2.4% ( 95% CI )-Garcia-Velasco et al.,2000Non- stop vs. stop protocolPregnancy rate : 13.9% vs. 17.6%Rate difference: 3.7% ( 95% CI to +13.7)
114The modifications of the long agonist protocol described Dirnfeld et al.,1999Garcia-Velasco et al.,2000ConclusionThe modifications of the long agonist protocol describeddo not appear to enhance the probability of pregnancyover the conventional long protocol
115Background: Suppression of premature LH surge: Short protocol: promotes follicular growth by taking advantage of the flare- up effect of GnRH-agonist on pituitary gonadotrophin releaseLong protocol:results in a more coordinated follicular growth.
116Relevant study: Weissman et al .,2003 N:60 patientsProtocol:Short protocol: a high dose of GnRH-a for 4 days, followed by standard GnRH-a doseLong protocol: a standard GnRH-a dose was used until pituitary down- regulation, following by halving the GnRH-a doseDefinition of poor response : presence of fewer than 5 oocytes retrieved or three or fewer follicles of 16mm or larger developed on the day of cycle cancellation, or serum E2 level < 500pg/ml on the day of HCG administrationOutcome :clinical pregnancy rate
117Weissman et al .,2003Mini-dose long protocol vs. modified short protocolClinical pregnancy rate/ started cycle: 22,6% vs 3,4% p=0.053Rate difference: +19.2% ( 95% CI: to +38.6)
118The two protocols appear to yield the same results Weissman et al .,2003ConclusionThe two protocols appear to yield the same resultsin poor responders undergoing IVF
119Background:GnRH antagonist prevent the suppression of endogenous gonadotrophin secretion at the stage of follicular recruitment(Craft et al., 1999; Tarlatzis et al., 2003).
120GnRH-antagonists in poor responders Griesinger et al 2006Relevant studies:8Total N: 575 patientsProtocols: 2 studies→ long agonist protocol6 studies → flare-up protocolDefinition of poor response:In the majority of studies →“inappropriate ovarian response” during a previous stimulated cycle.Only in two studies→ age of the patients and the basal FSH concentrations used as criteriaOutcome: clinical pregnancy rate, COCs
121Clinical pregnancy rate GnRH-antagonists in poor respondersGriesinger et al 2006.Agonist vs.antagonistClinical pregnancy rateOR=1.28(95% CI: )
122GnRH-antagonists in poor responders Griesinger et al 2006Long agonist group vs. GnRH-ant groupCOCsSDF (95 % CI: )
123GnRH-antagonists in poor responders Griesinger et al 2006ConclusionNo difference in pregnancy rates appears to existbetween GnRH agonists and antagonistsin poor responder patients
124Relevant study: Akman et al.,2000 N: 40 patientsProtocol: GnRH-ant/FSH+HMG vs FSH+HMGQuasi-randomizationDefinition of poor response : at least two previous IVF attempts with low response due to the one of the following reasons: baseline FSH concentrations >15mIU/ml, E2 on the day of HCG < 500pg/ml, or fewer than four oocytes retrievedOutcome : ongoing pregnancy rate
125GnRH antagonist group vs. control group Akman et al.,2000GnRH antagonist group vs. control groupClinical pregnancy rate: 20.0% vs. 6.2%
126The addition of GnRH antagonists to ovarian stimulation ConclusionThe addition of GnRH antagonists to ovarian stimulationdoes not appear to offer any benefitin poor responder patients undergoing IVF
127Background: Short agonist vs. natural cycle the use of natural cycle IVF in poor responder patients as alternative to COH and oocyte donation:→less invasive→ less costly
128Short agonist vs. natural cycle Relevant study: Morgia et al .,2004N: 129 patientsProtocol: natural cycle versus a short agonist protocolDefinition of poor response : retrieval of three or fewer oocytes in a previous attempt or cancellation of the cycle because of no follicular developmentOutcome : pregnancy rate
129Short agonist vs. natural cycle Morgia et al .,2004Natural cycle vs. short agonistPregnancy rate: 6.1% vs. 6.9%, respectivelyRate difference: 0.8% (95% CI: -8.2 to +6.2)
130Short agonist vs. natural cycle Morgia et al .,2004ConclusionNo beneficial effect of natural cycle compared to short agonist protocol in poor responders
131High vs standard dose of FSH High vs decremental dose of FSH
132Relevant study: Cedrin-Durnerin et al., 2000 N: 96 patients Protocol: high fixed dose of gonadotropins versus a decremental dose in a short mini-dose GnRH-a protocolDefinition of poor response : retrieval of fewer of five oocytes in a previous IVF cycle or elevated baseline FSH or E2 levels on cycle day 3Outcome : pregnancy rateRelevant study: Klinkert et al .,2005N: 52 patientsProtocol: higher starting dose of gonadotrophins during a long GnRH –a protocolDefinition of poor response : the presence of fewer than four oocytes retrieved or fewer than three follicles developed on the day of cycle cancellationOutcome :ongoing pregnancy ratecedrin durnerin not retrospectiveklinkert AFC definition
133Cedrin-Durnerin et al., 2000Decremental group vs.high fixed dose groupPregnancy rate: 6.25% vs. 8.33%Rate difference: 2.08 (95% CI: to +9.64)Klinkert et al .,2005Standard dose of FSH vs. double doseOngoing pregnancy rate: 7.69% vs. 3.85%Rate difference: 3.84 ( 95% CI: to )
134A high fixed-dose gonadotrophin regimen Cedrin-Durnerin et al., 2000Klinkert et al .,2005ConclusionA high fixed-dose gonadotrophin regimendoes not improve the pregnancy ratein poor responder patients
135Initiation of FSH during the luteal phase Background:B) The antral follicles are present in late follicular phase of the ovarian cycle and initiation of their further development occurs under the action of the premenstrual FSH rise(Gougeon et al, 1996)Rationale:Earlier administration of FSH might ↑ the number of recruited follicles by opening the recruitment window in the late luteal phase of the preceding cycle
136Relevant study: Rombauts et al., 1998 N:40 patientsProtocol: initiating FSH during the luteal phaseDefinition of poor response : retrieval of three to six oocytes in the last FSH stimulated IVF or GIFT cycle.Outcome : COCs
137Luteal initiation of FSH vs. follicular initiation of FSH Rombauts et al., 1998Luteal initiation of FSH vs. follicular initiation of FSHNumber of oocytes retrieved/cycle :median: 4.5, range: vs. median: 6, range: 1-10no data on pregnancy rate
138The administration of FSH in the luteal phase Rombauts et al., 1998ConclusionThe administration of FSH in the luteal phasehas no beneficial effect on the total number of oocytes retrievedin poor responder patients
139Background Available evidence is not able to demonstrate whether ICSI is more efficacious than conventional IVFin poor responder patients(Van Steirteghem 1993)
140Relevant study: Moreno et al.,1998 N: 104 patientsProtocol: long GnRH-a protocol/HMG+FSH.Fertization method: ICSI or IVFDefinition of poor response: retrieval of six or fewer oocytes in a previous cycle.Outcome : pregnancy rate
141Rate difference: -3.8% ( 95% CI -18.9 to +11. 4) Moreno et al.,1998IVF vs. ICSIPregnancy rate : 17.3% vs. 21.1%Rate difference: -3.8% ( 95% CI to )
142are not dependent on the fertilization method in poor responders, Moreno et al.,1998ConclusionPregnancy ratesare not dependent on the fertilizationmethod in poor responders,however more studies are necessary
143The management of poor responders still represents a challenge for the clinician, which is further complicated by the variations in the definition of poor ovarian responseWith the exception of GH co-administration, none of the examined approaches appears to be beneficialDue to the low incidence of poor ovarian response, evaluation of the interventions proposed is usually performed in single, underpowered studies, which might not allow the detection of the true effect of an intervention